Adenosine receptors are involved in a vast number of peripheral and central regulatory mechanisms such as, for example, vasodilation, cardiac depression, inhibition of lipolysis, inhibition of insulin release and potentiation of glucagon release in the pancreas, and inhibition of neurotransmitter release from nerve endings.
In general, adenosine receptors can be divided into two main classes, A1 receptors which can inhibit, and A2 receptors which can stimulate adenylate cyclase activity. One of the best known classes of adenosine receptor antagonists are the xanthines which include caffeine and theophylline. See e.g., Müller et al., J. Med. Chem. 33: 2822–2828 (1990). In general, many of these antagonists often suffer from poor water solubility, and low potency or lack of selectivity for adenosine receptors. Additionally, selective analogues of adenosine receptor antagonists have been developed through the “functionalized congener” approach. Analogues of adenosine receptor ligands bearing functionalized chains have been synthesized and attached covalently to various organic moieties such as amines and peptides. Attachment of the polar groups to xanthine congeners has been found to increase water solubility. Nonetheless, such developments have yet to fully address problems associated with potency and selectivity. More recently Jacobson et al. J. Med. Chem. 35: 408–422 (1992) has proposed various derivatives of adenosine and theophylline for use as receptor antagonists. The article discloses that hydrophobic substituents are able to potentially enhance affinity. However, it is also acknowledged that such substituents may result in a decrease in solubility thus rendering the antagonists less soluble in vivo. In confronting these problems, Jacobson et al. indicates that a dipropyl substitution at the 1 and 3 positions of theophylline allows desirable affinity at A1 receptors. It is also stated that substitutions at the 7-position are typically not favorable.
Selective analogues of adenosine receptor antagonists have been developed through the “functionalized congener” approach. See e.g., U.S. Pat. No. 4,968,672 to Jacobson et al.; and Jacobson et al., Mol. Pharmacol. 29: 126–133 (1985). In terms of pharmacology, the compounds advantageously display increased affinity at A1 receptor sites relative to former A1 receptor antagonists while simultaneously exhibiting good water solubility.
U.S. Pat. No. 5,786,360 to Neely describes A1 adenosine receptor antagonists.
U.S. Pat. No. 6,489,332 to Neely describes A1 adenosine receptor antagonists.
U.S. Pat. No. 5,719,279 to Kufner-Muhl et al. describes certain xanthine derivatives that have A1 adenosine receptor affinity.
It is an object of the present invention to provide additional compounds useful as A1 adenosine receptor antagonists, preferably compounds with good water solubility.